SELECTIVE-INHIBITION OF EXPRESSION OF THE CHEMOKINE RECEPTOR CCR2 IN HUMAN MONOCYTES BY IFN-GAMMA

IFN-gamma is a potent activator of mononuclear phagocyte function and promotes the development of Th1 responses. Moreover, it induces and mo dulates chemokine production in a variety of cell types, including mon onuclear phagocytes. In the present study, we examined the effect of I FN-gamma on the expression of CC chemokine receptors in human monocyte s, IFN-gamma selectively and rapidly inhibited expression of the monoc yte chemotactic protein (MCP) receptor CCR2 with an ED50 of similar to 50 U/ml, The effect was rapid (detectable after 1 h) and reversible, Other chemokine receptors (CCR1, CCR3, CCR4, and CCR5) were not substa ntially affected, and CXCR4 was reduced. IFN-gamma acted in concert wi th LPS, TNF-alpha, and IL-1 beta in inhibiting CCR2 expression. IFN-ga mma-treated monocytes showed a shorter half-life of CCR2 mRNA compared ,vith untreated cells, whereas the rate of nuclear transcription was u naffected, The inhibition of CCR2 mRNA expression by IFN-gamma was ass ociated with a lower number of surface receptors and lower chemotactic responsiveness, Thus, IFN-gamma an inducer of MCP-1 and MCP-3 in mono nuclear phagocytes, selectively inhibits expression of the MCP recepto r CCR2 in monocytes, These results are consistent with an emerging par adigm of divergent regulation by several agents of chemokine productio n and receptor expression in monocytes. The inhibition of MCP-1R expre ssion may serve as a means of retaining mononuclear phagocytes at site s of inflammation and as a feedback mechanism in the regulation of rec ruitment from the blood.